The research team, led by David Liu, professor of chemistry and chemical biology at Harvard University, core institute member at the Broad Institute, and a Howard Hughes Medical Institute investigator, developed a molecular machine that can convert the DNA base pair AT to GC, without cutting the double helix, with high efficiency and virtually no undesired products.
The new system, dubbed Adenine Base Editor, or ABE, can be programmed to target a specific base pair in a genome using a guide RNA and a modified form of CRISPR-Cas9. As a result, what used to be an AT base pair becomes a GC base pair.
Making this specific change is important because approximately half of the 32,000 disease-associated point mutations already identified by researchers are a change from GC to AT. “We developed a new base editor – a molecular machine – that in a programmable, irreversible, efficient, and clean manner can correct these mutations in the genome of living cells,” said Liu, who is also the Richard Merkin Professor and Director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad. “When targeted to certain sites in human genomic DNA, this conversion reverses the mutation that is associated with a particular disease.”
Using these base editors, researchers can now correct all the so-called “Transition” mutations – C to T, T to C, A to G, or G to A – that together account for almost two-thirds of all disease-causing point mutations, including many that cause serious illnesses for which there are no current treatments.
Development of the new base editor began when the team began a year-long effort to evolve a new enzyme that could convert adenine into inosine, a nucleotide that behaves similarly to G during DNA or RNA synthesis.
While the development of ABE is an exciting step forward in base editing, more work remains before base editing can be used to treat patients with genetic diseases, including tests of safety, efficacy, and side effects.